Agarofuran compound, preparation method therefor, and application thereof

Abstract

Embodiments of the present application relate to an agarofuran compound, a preparation method therefor, and an application thereof. In the embodiments of the present application, structural modification is performed on main metabolic sites, such as alkyl side chain, of 4-butyl-α-agarofuran (BAF) to provide a novel agarofuran compound having higher activity, a better therapeutic effect, and better drug metabolism properties to treat mental illnesses such as anxiety disorders.

1 - 10 . (canceled) 
     
     
         11 . An agarofuran-based compound, having a structural formula (I): 
       
         
           
           
               
               
           
         
         wherein there is no double bond in the ring A or there is one double bond located in the position 2-3 of the ring A; 
         R 1  is methyl that is monosubstituted, disubstituted, or trisubstituted by fluorine atom(s); 
         R 2  is C 2 -C 9  linear hydrocarbylene, branched hydrocarbylene or cycloalkylene that is unsubstituted, hydroxyl-substituted or carbonyl-substituted, and the linear hydrocarbylene or branched hydrocarbylene is alkylene or alkenylene containing 1-3 double bonds; 
         m represents the number of R 3  groups linked to carbon in the position 4 of the ring A, m=1 or 2, and when m=1, R 3  is selected from hydrogen atom, carbonyl, or hydroxyl; when m=2, R 3  is deuterium atom; and 
         R 4  is selected from hydrogen atom, deuterium atom, carbonyl or hydroxyl. 
       
     
     
         12 . The agarofuran-based compound according to  claim 11 , wherein R 2  is C 2 -C 5  linear alkylene that is unsubstituted, hydroxyl-substituted, or carbonyl-substituted; optionally, R 2  is C 3 -C 4  linear alkylene that is unsubstituted, hydroxyl-substituted, or carbonyl-substituted; and further optionally, R 2  is C 3  linear alkylene that is unsubstituted, hydroxyl-substituted, or carbonyl-sub stituted. 
     
     
         13 . The agarofuran-based compound according to  claim 11 , wherein it is selected from the following compounds: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A use of the agarofuran-based compound according to  claim 11 , the pharmaceutically acceptable salt thereof, the prodrug thereof, or the pharmaceutical composition comprising the same in preparation of a drug for preventing and/or treating an anxiety disorder. 
     
     
         15 . A use of the agarofuran-based compound according to  claim 12 , the pharmaceutically acceptable salt thereof, the prodrug thereof, or the pharmaceutical composition comprising the same in preparation of a drug for preventing and/or treating an anxiety disorder. 
     
     
         16 . A use of the agarofuran-based compound according to  claim 13 , the pharmaceutically acceptable salt thereof, the prodrug thereof, or the pharmaceutical composition comprising the same in preparation of a drug for preventing and/or treating an anxiety disorder. 
     
     
         17 . A preparation method for the agarofuran-based compound according to  claim 11 , wherein the preparation method is selected from any one of the followings:
 (1) when there is one double bond located in the position 2-3 of the ring A of the agarofuran-based compound shown in General formula (I), m=1, and R 3  and R 4  are both hydrogen atoms, the preparation method comprises the following steps:   
       
         
           
           
               
               
           
         
         wherein, compounds shown in Formulas (I-a) and (I-b) are subjected to a substitution reaction under an alkaline condition, to obtain a compound shown in Formula (I-c); Ri is methyl that is monosubstituted, disubstituted, or trisubstituted by fluorine atom(s); R 2  is C 2 -C 9  linear hydrocarbylene, branched hydrocarbylene or cycloalkylene that is unsubstituted, hydroxyl-substituted or carbonyl-substituted, and the linear hydrocarbylene or branched hydrocarbylene is alkylene or alkenylene containing 1-3 double bonds; X is halogen, preferably bromine; 
         the compound shown in Formula (I-c) is subjected to a reduction reaction in the presence of a reducing agent, to obtain a compound shown in Formula (I-d); and 
         the compound shown in Formula (I-d) is subjected to a cyclization reaction under an acidic condition, to obtain a compound in Formula (I-e); 
         (2) when there is no double bond in the ring A of the agarofuran-based compound shown in General formula (I), m=1, and R 3  and R 4  are both hydrogen, the preparation method comprises the following steps: the compound (I-e) in the preparation method (1) is subjected to catalytic hydrogenation to obtain a compound shown in Formula (I-f); 
       
       
         
           
           
               
               
           
         
         (3) when there is one double bond located in the position 2-3 of the ring A of the agarofuran-based compound shown in General formula (I), m=2, and R 3  and R 4  are both deuterium, the preparation method comprises the following steps: 
       
       
         
           
           
               
               
           
         
         wherein, compounds shown in Formulas (I-a) and (I-b) are subjected to a substitution reaction under an alkaline condition, to obtain a compound shown in Formula (I-c); R 1  is methyl that is monosubstituted, disubstituted, or trisubstituted by fluorine atom(s); R 2  is C 2 -C 9  linear hydrocarbylene, branched hydrocarbylene or cycloalkylene that is unsubstituted, hydroxyl-substitutedor carbonyl-substituted, and the linear hydrocarbylene or branched hydrocarbylene is alkylene or alkenylene containing 1-3 double bonds; X is halogen, preferably bromine; 
         the compound shown in Formula (I-c) is subjected to a deuteration reaction with deuterated alcohol under an alkaline condition, to generate a compound shown in Formula (I-j); 
         the compound shown in Formula (I j) is subjected to a reduction reaction in the presence of a reducing agent, to obtain a compound shown in Formula (I-g); and 
         the compound shown in Formula (I-g) is subjected to a cyclization reaction under an acidic condition, to obtain a compound shown in Formula (I-h); 
         (4) when there is no double bond in the ring A of the agarofuran-based compound shown in General formula (I), m=2, and R 3  and R 4  are both deuterium, the preparation method comprises the following steps: the compound (I-h) in the preparation method (3) is subjected to catalytic hydrogenation to obtain a compound shown in Formula (I-i); 
       
       
         
           
           
               
               
           
         
         (5) when there is one double bond in the ring A of the agarofuran-based compound shown in General formula (I), m=1, R 3  is carbonyl, and R 4  is hydrogen, the preparation method comprises the following steps: the compound shown in Formula (I-e) in the preparation method (1) is subjected to an oxidation reaction in the presence of an oxidant, to obtain a compound shown in Formula (I-k); 
       
       
         
           
           
               
               
           
         
         (6) when there is one double bond in the ring A of the agarofuran-based compound shown in General formula (I), m=1, R 3  is hydroxyl, and R 4  is hydrogen, the preparation method comprises the following steps: the compound shown in Formula (I-k) in the preparation method (5) is subjected to a reduction reaction in the presence of a reducing agent, to obtain a compound shown in Formula (I-m); 
       
       
         
           
           
               
               
           
         
       
     
     
         18 . The preparation method according to  claim 17 , wherein R 2  is C 2 -C 5  linear alkylene that is unsubstituted, hydroxyl-substituted, or carbonyl-substituted; optionally, R 2  is C 3 -C 4  linear alkylene that is unsubstituted, hydroxyl-substituted, or carbonyl-substituted; and further optionally, R 2  is C 3  linear alkylene that is unsubstituted, hydroxyl-substituted, or carbonyl-substituted. 
     
     
         19 . The preparation method according to  claim 17 , wherein Ri and R 2  are selected from any one of the following combinations:
   R 1 =—CF 3 , R 2 =—CH 2 CH 2 CH 2 —  1.
     R 1 =—CF 2 , R 2 =—CH 2 CH 2 CH 2 —  2.
     R 1 =—CH 2 F, R 2 =—CH 2 CH 2 CH 2 —  3.
     R 1 =—CF 3 , R 2 =—CH 2 CH 2 CH 2 CH2—  4.
   
     
     
         20 . The preparation method according to  claim 17 , wherein the reagent for providing an alkaline condition comprises an inorganic base, and the inorganic base comprises: one or more of sodium hydride, sodium hydroxide, potassium hydroxide, sodium tert-butanol, and potassium tert-butanol;
 and/or, the reducing agent comprises: one or more of sodium borohydride, potassium borohydride, and lithium aluminum hydride;   and/or, the reagent for providing an acidic condition comprises: one or more of trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid and p-toluenesulfonic acid;   and/or, the metal catalyst for the catalytic hydrogenation comprises: one or more of palladium carbon, rhodium carbon, platinum dioxide, and Raney nickel;   and/or, the oxidant for the oxidation reaction comprises: one or more of oxygen, hydrogen peroxide, peroxide, and Sarrett reagent.   
     
     
         21 . The preparation method according to  claim 17 , wherein the solvents used in the preparation method (1) comprise: Step 1: one or more of methanol, ethanol, isopropanol, and tert-butanol; Step 2: one or more of ether and tetrahydrofuran; and Step 3: one or more of n-hexane and petroleum ether;
 and/or, the solvent used in the preparation method (2) comprises: one or more of ethanol, methanol, and ether;   and/or, the solvents used in the preparation method (3) comprise: Step 1: one or more of methanol, ethanol, isopropanol, and tert-butanol; Step 2: one or more of deuterated methanol and deuterated ethanol; Step 3: one or more of ether and tetrahydrofuran; and Step 4: one or more of n-hexane and petroleum ether. and/or, the solvent used in the preparation method (4) comprises: one or more of ethanol, methanol, and ether;   and/or, the solvent used in the preparation method (5) comprises: one or more of dichloromethane, toluene, benzene, and pyridine;   and/or, the solvent used in the preparation method (6) comprises: one or more of ethanol, methanol, and ether.